Sandbox Reserved 817: Difference between revisions
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Surprisingly, a compound which has an acetamide group between two chlorine atoms showed a more substantial increase in potency. If two chlorine atoms are remplaced with two hydrogen atoms or reduced the amide to an amine, the resulting compounds displayed much weaker activities against BACE1. The acetamide nitrogen atom forms another hydrogen bond directly with the main chain carboxyl oxygen of <scene name='56/568015/Phe108/1'>Phe108</scene>. The two chlorine atoms may force the acetamide group adopting a perpendicular angle with respect to the benzyl group, which plays an important role in binding interactions between acetamide and BACE1.Besides, the hydrogen bonds of the inhibitor with residues <scene name='56/568015/Gln73/1'>Gln73d</scene> and <scene name='56/568015/Thr72/1'>Thr72</scene> induce a semi-closed conformation. Such a conformation of the flap further strengthens the ligand binding to the enzyme. | Surprisingly, a compound which has an acetamide group between two chlorine atoms showed a more substantial increase in potency. If two chlorine atoms are remplaced with two hydrogen atoms or reduced the amide to an amine, the resulting compounds displayed much weaker activities against BACE1. The acetamide nitrogen atom forms another hydrogen bond directly with the main chain carboxyl oxygen of <scene name='56/568015/Phe108/1'>Phe108</scene>. The two chlorine atoms may force the acetamide group adopting a perpendicular angle with respect to the benzyl group, which plays an important role in binding interactions between acetamide and BACE1.Besides, the hydrogen bonds of the inhibitor with residues <scene name='56/568015/Gln73/1'>Gln73d</scene> and <scene name='56/568015/Thr72/1'>Thr72</scene> induce a semi-closed conformation. Such a conformation of the flap further strengthens the ligand binding to the enzyme. | ||
Analogs were also synthesized based on indole | Analogs were also synthesized based on indole. The indole group pointed toward the back of the S1’ pocket forming a cation-πinteraction with <scene name='56/568015/Arg235/1'>Arg235</scene>, which appears to contribute further interactions to improve the potency of the inhibitor. <ref name="three">PMID:23681056</ref> | ||
The indole group pointed toward the back of the S1’ pocket forming a cation-πinteraction with <scene name='56/568015/Arg235/1'>Arg235</scene>, which appears to contribute further interactions to improve the potency of the inhibitor. <ref name="three">PMID:23681056</ref> | |||
